Your browser doesn't support javascript.
loading
In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy.
Arlauckas, Sean P; Garris, Christopher S; Kohler, Rainer H; Kitaoka, Maya; Cuccarese, Michael F; Yang, Katherine S; Miller, Miles A; Carlson, Jonathan C; Freeman, Gordon J; Anthony, Robert M; Weissleder, Ralph; Pittet, Mikael J.
Afiliación
  • Arlauckas SP; Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5206, Boston, MA 02114, USA.
  • Garris CS; Department of Radiology, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5206, Boston, MA 02114, USA.
  • Kohler RH; Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
  • Kitaoka M; Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5206, Boston, MA 02114, USA.
  • Cuccarese MF; Graduate Program in Immunology, Harvard Medical School, Boston, MA 02115, USA.
  • Yang KS; Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5206, Boston, MA 02114, USA.
  • Miller MA; Center for Immunology and Infectious Disease, Massachusetts General Hospital, 149 8th Street, Charlestown, MA 02129, USA.
  • Carlson JC; Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5206, Boston, MA 02114, USA.
  • Freeman GJ; Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5206, Boston, MA 02114, USA.
  • Anthony RM; Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5206, Boston, MA 02114, USA.
  • Weissleder R; Department of Radiology, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5206, Boston, MA 02114, USA.
  • Pittet MJ; Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5206, Boston, MA 02114, USA.
Sci Transl Med ; 9(389)2017 05 10.
Article en En | MEDLINE | ID: mdl-28490665
Monoclonal antibodies (mAbs) targeting the immune checkpoint anti-programmed cell death protein 1 (aPD-1) have demonstrated impressive benefits for the treatment of some cancers; however, these drugs are not always effective, and we still have a limited understanding of the mechanisms that contribute to their efficacy or lack thereof. We used in vivo imaging to uncover the fate and activity of aPD-1 mAbs in real time and at subcellular resolution in mice. We show that aPD-1 mAbs effectively bind PD-1+ tumor-infiltrating CD8+ T cells at early time points after administration. However, this engagement is transient, and aPD-1 mAbs are captured within minutes from the T cell surface by PD-1- tumor-associated macrophages. We further show that macrophage accrual of aPD-1 mAbs depends both on the drug's Fc domain glycan and on Fcγ receptors (FcγRs) expressed by host myeloid cells and extend these findings to the human setting. Finally, we demonstrate that in vivo blockade of FcγRs before aPD-1 mAb administration substantially prolongs aPD-1 mAb binding to tumor-infiltrating CD8+ T cells and enhances immunotherapy-induced tumor regression in mice. These investigations yield insight into aPD-1 target engagement in vivo and identify specific Fc/FcγR interactions that can be modulated to improve checkpoint blockade therapy.
Asunto(s)
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptor de Muerte Celular Programada 1 / Anticuerpos Monoclonales Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptor de Muerte Celular Programada 1 / Anticuerpos Monoclonales Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos